Biomol Ther.  2017 Mar;25(2):112-121. 10.4062/biomolther.2016.076.

Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity

• Kim M
• Yun JW
• Shin K
• Cho Y
• Yang M
• Nam KT
• Lim KM

• KMID: 2375030
• DOI: http://doi.org/10.4062/biomolther.2016.076

Abstract

Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix GeneChip® Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.

Keyword

Acetaminophen; Hepatotoxicity; Toxicogenomics; GABA-A receptor subunit alpha 3; Lipoprotein lipase

MeSH Terms

Acetaminophen
Animals
Drug-Induced Liver Injury
Genetic Variation
Incidence
Lipoprotein Lipase*
Lipoproteins*
Liver
Methods
Mice
Microarray Analysis
Real-Time Polymerase Chain Reaction
Receptors, GABA-A*
Toxicogenetics
Transcriptome
Acetaminophen
Lipoprotein Lipase
Lipoproteins
Receptors, GABA-A